ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome

Makito Hirano, Yoshiko Furiya, Hirohide Asai, Akira Yasui, Satoshi Ueno

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)


Triple A syndrome is an aufosomal recessive neuroendocrinological disease caused by mutations in a gene that encodes 546 amino acid residues. The encoded protein is the nucleoporin ALADIN, a component of nuclear pore complex (NPC). We identified a mutant ALADINI482S that fails to target NPC and investigated the consequences of mistargeting using cultured fibroblasts (I482Sf) from a patient with triple A syndrome. ALADINI482S affected a karyopherin-α/β-mediated import pathway and decreased nuclear accumulations of aprataxin (APTX), a repair protein for DNA single-strand breaks (SSBs), and of DNA ligase I in I482Sf. This decrease was restored by wild-type ALADIN. ALADINI482S had no effect on imports of M9/kap-β2, BIB/kap-β3, histone H1/importin 7, the ubiquitin conjugating enzyme UbcM2 importin 11, or the spliceosome protein U1A, indicating that ALADIN I482S selectively impaired transport of discrete import complexes through NPC. Cell survival assay showed hypersensitivity of I482Sf to L-buthionine-(S,R)-sulfoximine (BSO), a glutathione-depleting agent. BSO decreased nuclear APTX and ligase I levels in I482Sf and normal control fibroblasts, but increased SSBs only in I482Sf. These observations implied that I482Sf are hypersensitive to BSO and no longer sufficiently repair SSBs. Consistent with this notion, I482Sf transfected with both APTX and ligase I had increased resistance to BSO, whereas I482Sf transfected with LacZ vector remained hypersensitive to BSO. We propose that oxidative stress aggravates nuclear import failure, which is already compromised in patient cells. Consequent DNA damage, beyond the limited capacity of DNA repair proteins, i.e., APTX and ligase I, may participate in triggering cell death.

Original languageEnglish
Pages (from-to)2298-2303
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
Publication statusPublished - 2006 Feb 14
Externally publishedYes


  • Aprataxin
  • DNA ligase I
  • Nuclear pore complex

ASJC Scopus subject areas

  • General


Dive into the research topics of 'ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome'. Together they form a unique fingerprint.

Cite this